Monkeypox outbreaks

Monkeypox outbreaks: a wake-up call to?everyone

by Maurizio Ferri

Highlights

• Monkeypox, a rare zoonotic disease found in animal reservoirs and endemic to sub-Saharan Africa, made its appearance in May 2022 in Europe and other high-income countries with the largest epidemics that led WHO to declare it a public health emergency of international concern (PHEIC) marked by an increasing number of outbreaks globally.
• About 98% of infections globally affect people who identify as gay, bisexual, or men having sex with men (MSM), with sporadic reports in women and children
• Before the current outbreak, monkeypox infections in Africa had been assumed to be primarily caused by exposure to animal reservoirs, despite human-to-human transmissions also being documented
• For the current outbreaks in non-endemic regions, there is no evidence of the presence of an animal reservoir or transmission of the infection to humans (spillover). The first case of spillback from humans to a domesticated dog has recently been reported in France.

Monkeypox disease is a rare zoonotic infection caused by the monkeypox virus, an Orthopoxvirus (DNA virus) belonging to the same poxviridae family of the variola virus, the etiological agent of smallpox, one of the most deadly diseases in human history that was fully eradicated in the early 1980s following a massive vaccination campaign. Monkeypox virus was initially discovered and described in 1958 in Denmark during an investigation of an infectious outbreak affecting monkey colonies. The first human case was reported in 1970 in the Democratic Republic of the Congo, and the virus has since spread to eleven African countries, notably in some regions of Central and Western Africa, where it is endemic. Monkeypox virus includes two genetic clades, namely West Africa and Central Africa (also called Congo Basin) clades, the latter being more virulent as it has a case fatality rate up to 10%. Although the natural reservoir is unknown, the disease is attributable to spillover events to humans from animals, such as squirrels, rats, mice, monkeys, and prairie dogs. Human-to-human transmission was also documented in 1996–1997 in the Democratic Republic of Congo. Outside Africa, a cluster of 47 cases related to infected pet prairie dogs was described in the United States, associated with the importation of contaminated rodents and other exotic animals from Ghana. Subsequently, further outbreaks have been reported in the UK, Israel, and Singapore.

Starting from May 22, 2022, the first cases with no contact with Africa were reported, , predominantly, but not exclusively, among young gay and bisexual men without a travel history to endemic regions in Central and West Africa and with no evident epidemiological link between reported cases. Some of these cases have now been epidemiologically linked to participation in mass gathering events/festivals, like the “Maspalomas (Gran Canaria) 2022 pride”.

The monkeypox outbreaks in non-endemic countries are driven, thankfully, by the West African clade, which is less virulent than the Central African clade and results in lower inter-human transmission. Before the current outbreak, monkeypox infections had been assumed to be primarily caused by exposure to animal reservoirs with relatively few cases associated with human-to-human transmission via direct routes including skin-to-skin contact, bodily fluids, and respiratory droplets.

In Europe, the first case was notified by the United Kingdom on May 7, 2022. Since then, cases have increased exponentially in the United Kingdom and in other countries: Spain, the United States, Germany, France, Netherlands, Canada, Brazil, Portugal, and Italy. Two deaths have been reported in Spain.?

On 23 July 2022, monkeypox was declared a PHEIC by WHO Director-General Tedros Adhanom Ghebreyesus. This is the seventh declaration of a PHEIC since 2005, a condition when a disease outbreak is an extraordinary event, it constitutes a public health risk to other states through international spread, and a coordinated international response is potentially required. The WHO declaration signals a public health risk that must be managed by the commitment of member countries to invest significant resources into the control of outbreaks and to share vaccines, drugs, and other key resources.

Americas is the epicenter of the?epidemic

In the early stages of the outbreak in non-endemic countries, Europe was the epicenter, with a smaller proportion of cases in the Region of the Americas. Now, according to WHO data, reported cases are rising in the latter (71.4%) compared to the European Region (27.6%), making the Americas the main hot spot. As of 7 September 2022, a total of 54,707 laboratory-confirmed cases and 397 probable cases, including 18 deaths, have been reported. For Europe, the joint ECDC-WHO Regional Office reported a total of 22,363 cases of monkeypox from 43 countries and areas throughout the European Region up to 30 August 2022.

Groups at risk, virus transmission, symptoms, prevention, and?therapy?

Globally, about 98% of infections affect people predominantly aged between 18-50 years, who identify as gay, bisexual, or simply men having sex with men (MSM), especially those with multiple sexual partners. At present, there is no signal suggesting sustained transmission beyond these networks. Sporadic cases have also been reported in women and children. As for the transmission rate, it is estimated that the current monkeypox virus strain spreads much faster than the strains circulating before 2022. The virus is transmitted through direct contact with skin lesions, body fluids (especially during sexual intercourse), or by touching contaminated objects or fabrics. The virus can also spread through respiratory droplets produced when an infected person coughs or sneezes, but only with close and prolonged contact. The virus can be transmitted by pregnant women to their fetus through the placenta. The incubation period is from 5 to 21 days, and the symptoms, similar to smallpox but much less severe, are flu-like with fever (rare), headache, muscle ache, swollen lymph nodes, lethargy, and progression to skin blisters (and a pustular rash that is indistinguishable from smallpox) at the primary infection site on the head area, legs, and palms; this rash appears on the genital area when the virus is transmitted through sexual intercourse. Monkeypox virus has been reported to have several ophthalmic manifestations. Complications of monkeypox include pneumonitis, encephalitis, sight-threatening keratitis, and secondary bacterial infections. Based on the risk assessment carried out by ECDC for the cases in the European Union/European Economic Area, the likelihood of monkeypox virus spreading further is considered high in networks of people with multiple sexual partners but very low among the broader population.

As for prevention, early diagnosis, isolation, effective contact tracing, and targeted vaccination strategies are key for the effective control of this outbreak. The current not-replicating vaccines against smallpox (e.g. Jynneos or Imvanex) have proven to be effective in preventing monkeypox or in attenuating disease outcomes as post-exposure prophylaxis. As for therapy, the antiviral drug tecovirimat, which in animals infected with monkeypox has been shown to lower the amount of virus in their bodies and reduce the number of skin lesions, seems to be effective in humans, despite data being limited. Clinical trials of tecovirimat are starting up now, but results are still months away. Other drugs, such as ciclofovir and brincidofovir, developed for smallpox, seem to work against monkeypox.

What is striking is the different picture of the cases in high-income countries compared to those in low-income African countries; in wealthy nations, cases frequently have localization of lesions in the anogenital area (urethra and rectum) (31.4% of monkeypox cases), and the absence of fever and respiratory symptoms; these differences could be linked to genome mutations. This hypothesis is partially confirmed by preliminary genetic analysis of virus strains from recently-infected patients, which have several mutations that the strains present before 2018 do not have. It is not clear whether this is significant for the mode of transmission, the severity of the infection, or other characteristics of the virus. Based on the available genetic information, the virus shows remarkable adaptability that could ease inter-human transmission, and a continuous accelerated evolution, with recent strains being segregated in a divergent phylogenetic branch compared to 2018–2019 lineages. Data are currently lacking on monkeypox outbreaks in high-income countries, and there are still gray areas around the dynamics of virus transmission, the role of asymptomatic patients, the divergence of symptoms from those in previous outbreaks, and the contagion through sperm or vaginal secretions (sexual transmission). Luckily, to date, the lethality rate of the virus is almost zero, unlike in Africa, where deaths make up 1–10% of cases. In low-income countries, the high death rates can reasonably be attributable to the lack of adequate health care and vaccination, and to either the very small population coverage of smallpox vaccination, which crosses protects against monkeypox or the waned immunity in smallpox-vaccinated individuals.

Could monkeypox be a new pandemic?

Monkeypox is a health global emergency but it cannot be likened to a pandemic such as Covid-19 for three main reasons: the virus has been known for some time; some vaccines provide good protection against monkeypox ?and; the virus has low transmissibility. However, the lack of a coordinated response between non-endemic countries to effectively tackle the outbreak might increase the risk of uncontrolled monkeypox virus spread, with potential complications and deaths among vulnerable populations, notably children, elderly, pregnant women, immunocompromised individuals, or those living with co-morbidities, such as HIV/AIDS and diabetes. There is also a problem of equitable distribution and access to vaccines and drugs, especially in countries with limited or no supplies.

Monkeypox moved from Africa to non-endemic countries

Monkeypox is an emerging zoonotic infection that is endemic in Africa. In the past two decades, outbreaks were notified in at least a dozen countries in West and Central Africa, in the latter, at a growing case rate. More than 60 cases and one death have been confirmed there this year. Notably, the re-emergence of monkeypox, particularly in Nigeria after more than three decades of no reported case, has been linked to the following conditions: (i) the lack of vaccination of the population against smallpox which cross protects against monkeypox, (ii) increased human encroachment on wildlife habitat due to urbanization and hunting that lead to human contact with the reservoirs, in particular rodents, and virus transmission via handling of infected animals for bushmeat consumption, (iii), use of medicines derived from wild animals, (iii) heavy rainfall and flooding that brings humans and monkeypox virus-infected animal hosts close together, (v) immunosuppression due to co-infection with HIV, and (iv) scarce diagnostic and therapeutic aids. To date, secondary transmission in endemic countries occurs through contact with body fluids or respiratory droplets of an infected person.

Before 2022, the West African clade of monkeypox made its way outside the African continent: three human cases were diagnosed in the United Kingdom, and additional cases were imported into Israel and Singapore from Nigeria. Both the reemergence of monkeypox in 2017 in Nigeria and the export of travelers’monkeypox from Nigeria to other parts of the world in 2018 and 2019 have raised the concern that the virus could have emerged and occupied the ecological and immunological niche vacated by smallpox virus. Indeed, this seems to have occurred in the ongoing monkeypox multi-country outbreak. Moreover, as shown by a recent study on the reconstruction and phylogenomic characterization of the first monkeypox outbreak genome sequences, the ongoing monkeypox outbreak most likely has a single origin, and the virus (lineage B.1), despite clustering with the 2018-2019 cases (West African clade 3), segregates in a divergent phylogenetic branch, reflecting its possible continuous accelerated evolution. It is also likely that, based on the study’s findings and the history of monkeypox epidemiology, the 2022 outbreak resulted from one or more importation events of the virus from endemic regions, potentially representing the continuous circulation and evolution of the virus that caused the 2017–2018 Nigeria outbreak.

The occurrence of a prolonged period of cryptic dissemination in humans or animals (or both) in a non-endemic country (for example, after the reported 2018–2019 imports from endemic regions) cannot be excluded. However, neither transmission in an animal host nor any related zoonotic spillover to humans seem to be associated with the ongoing monkeypox outbreaks. As current data show, it is more likely that from the cases pre-2022 (linked to one or more imports of the virus from endemic regions), the virus kept circulating in humans silently and was not detected promptly, and with the current outbreaks, it may have found its way into the MSM community.

Is the monkeypox an MSM-focused outbreak?

The key question stemming from the discussion among researchers is the following one: why is monkeypox virus causing such a big, multi-country outbreak, with the overwhelming majority of cases in the LGBTQI+ community? Current data collected from outbreak investigations and the results of contact tracing tell us that the likely drivers behind the worldwide surge of monkeypox outbreaks could simply be related, on the one hand, to the early introduction of the virus by travel from endemic countries into a new niche, the MSM population, marked by tightly interconnected social-sexual networks, and on the other hand, to amplification of monkeypox virus ?transmission through superspreader events (e.g., multi-sexual encounters at saunas, group sex, and other sexual practices involving multiple partners). This hypothesis is further supported by the results of an epidemiological modeling study conducted at the London School of Hygiene &Tropical Medicine, and the ECDC report. Both suggest that the probability of monkeypox spreading in networks of people who have multiple sexual partners is higher than in other people. The small fraction of individuals within the MSM community who have a disproportionately large number of partners could explain the sustained growth of monkeypox cases among MSM. It is also likely the striking pattern among MSM could be a skewed picture explained by their better relationship than heterosexual men with health care providers, as well as their better knowledge of sexual infectious diseases and uncommon conditions. This leads the MSM or LGBTQI+ community to be more likely to report symptoms and to demand to be tested for viruses. Opponents of this argument believe that such ascertainment bias is unlikely to explain the MSM-focused outbreak because the skin lesions and the associated agonizing pains, as well as the hospitalization, could not be overlooked in persons outside the MSM community.

A likely epidemiological scenario is that if the current sustained human-to-human transmission is not ended with prompt detection and containment, the infection could reach vulnerable groups (i.e., children and immunocompromised individuals) and vulnerable animals. Indeed, monkeypox virus is promiscuous and can infect various animals, in contrast to, say, variola virus, which has only humans as a host. From humans, monkeypox virus can move to susceptible domesticated and wildlife animal populations, particularly rodents and small mammals (spillback), where it could persist, become endemic in a region, and sporadically trigger new human infections. Worryingly, ?, such spillback has already occurred in France, where a dog in Paris caught monkeypox from one of its owners through direct contact with skin lesions.

What does this umpteenth zoonosis have to teach?us?

Despite a trend of decreasing weekly monkeypox cases, as at the end of August 2022, and reflecting the absolute need for a proper global response against the virus, the ongoing outbreaks in non-endemic regions should be a warning to governments to get well prepared for avoiding an emerging virus that can rapidly transcend national borders and become a global threat. Indeed, in the face of decades of constant outbreaks of monkeypox in endemic regions of Africa, and despite warnings issued by epidemiologists in the Democratic Republic of the Congo and Nigeria of an increase in infections, including the transmission linked to sexual contact, no effective action was undertaken in Africa to curtail the spread of the disease, and no vaccines are available against monkeypox.

To avoid mistakes similar to those made for Covid-19, which still poses global health challenges, non-endemic countries must work together to provide globally accessible and affordable vaccines against monkeypox, and ensure key interventions to control present and future outbreaks. The needed interventions are prevention (by administering smallpox vaccine), treatment, active surveillance, and monitoring of human infections. In addition to their national epidemic responses, high-income countries must provide sufficient resources to low- and middle-income countries, where the disease has historically been most prevalent and where vaccine supply and diagnostic capacity are patchy. Finally, to end this outbreak and prevent future ones in all countries, public health services must pursue a robust and coordinated response and share vaccines, therapeutics, testing, and expertise. Moreover, because monkeypox is a zoonotic disease, in the framework of the globally-driven One Health approach, governments must ensure communication and coordination of interventions among veterinary and wildlife services and public health services. This is particularly the case in endemic countries, where proper wildlife management practices must be implemented along with public health regulatory oversight over the trade of high-risk meats and products.